Inhibitor of citrate transporter and their use in therapy

Abstract

wherein R1 is Aryl, substituted aryl, styryl, or bicyclic; V is SO2; W is N with n and n1 are 1 and X is C═O, or W is C with n and n1 are 0 or 1 and X is CH2 or C═O, Y is N—H or N-methyl and R2 is benzyl, substituted benzyl or CH2(2-pyridyl). Further, it relates to the use of a compound of general formula (I) for preparing a medicament and its use for the treatment of obesity and diabetes, in particular type 2 diabetes and other metabolic diseases as well as for the treatment of age related diseases.

1 . A compound for use in a method for treating diseases depending on the activity of a citrate transporter, wherein the compound has the general formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         R1 is Aryl, substituted aryl, styryl, or bicyclic; 
         V is SO 2 ; 
         W is N with n and n1 are 1 and X is C═O, or 
         W is C with n and n1 are 0 or 1 and X is CH 2  or C═O; 
         Y is N—H or N-methyl; and 
         R2 is benzyl, substituted benzyl or CH 2 (2-pyridyl); 
         with the proviso that the compound of formula (I) is not the following compound: 
       
       
         
           
           
               
               
           
         
       
     
     
         2 . The compound of  claim 1 , wherein the compound is 1-(2-Phenyl-ethenesulfonyl)-azetidine-3-carboxylic acid 2-fluoro-benzylamide or 1-(3,5-dichlorobenzenesulfonyl)-N-[(4-fluorophenyl)methyl]piperidine-4-carboxamide. 
     
     
         3 . The compound of  claim 1 , wherein the compound inhibits the activity of the citrate transporter directly or allosterically. 
     
     
         4 . A compound, wherein the compound is 1-(2-Phenyl-ethenesulfonyl)-azetidine-3-carboxylic acid 2-fluoro-benzylamide. 
     
     
         5 . A compound of  claim 1  including pharmaceutically applicable salts, tautomers and stereoisomers of the compound, including mixtures thereof in all ratios for use in the treatment and/or prevention of diseases depending on the activity of a citrate transporter. 
     
     
         6 . The compound of  claim 5 , wherein the citrate transporter is the gene product of Indy or a homologue thereof. 
     
     
         7 . A compound according to  claim 1  for the treatment and/or prevention of
 a. metabolic diseases selected from the group comprising insulin resistance, alcoholic and non-alcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH), obesity, type 1 diabetes, type 2 diabetes, dyslipidemia, hereditary diseases and metabolic syndrome, and 
 b. eating disorders, and 
 c. chronic liver diseases, and 
 d. liver cancer and cancer related to obesity, and 
 e. drug induced hepatic steatosis. 
 
     
     
         8 . (canceled) 
     
     
         9 . A method for the treatment and/or prevention of age-related diseases or atherosclerosis and cardiovascular disease, cancer, arthritis, cataracts, osteoporosis, type 2 diabetes, hypertension, drug induced hepatic steatosis and neurodegenerative diseases like Alzheimer's disease comprising the step of administering a compound of general formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         R1 is Aryl, substituted aryl, styryl, or bicyclic; 
         V is SO 2 ; 
         W is N with n and n1 are 1 and X is C═O, or 
         W is C with n and n1 are 0 or 1 and X is CH 2  or C═O; 
         Y is N—H or N-methyl; and 
         R2 is benzyl, substituted benzyl or CH 2 (2-pyridyl). 
       
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . (canceled)